OBJECTIVES OF THE PROJECT: This resubmission of a VA Merit grant renewal continuously funded since 2005 focusing on understanding the basic mechanisms that underlie chronic pain and translating those findings into new therapeutic options for both male and female Veterans. This is important as current therapeutic approaches for treating our Veterans with chronic pain are largely ineffective due to a paucity of understanding of the mechanisms leading to chronic pain. RESEARCH PLAN & METHODOLOGY: This renewal application will build upon the novel findings from the parent grant and also takes advantage of cutting edge discovery approaches to delineate neural pathways and molecular mechanisms leading to stress-induced chronic pain. There is evidence of increased pain reporting in female veterans, thus specific Aim 1 will utilize state of the art approaches to test the hypothesis that sexually dimorphic epigenetic dysregulation in the central nucleus of the amygdala (CeA) underlies gene expression changes mediating the persistent effects of stress on visceral nociceptive processing. Under Specific Aim 2 we will take advantage of clinical evidence suggesting that chronic pain in patients can be reduced by psychological therapies such as biofeedback, relaxation training and yoga; however, the mechanisms by which such psychotherapies improve clinical pain are unknown. We will build upon our preliminary data showing the therapeutic potential of environmental enrichment to reverse stress-induced visceral pain by restoring corticotropin-releasing hormone (CRH), GR and mineralocorticoid receptor (MR) expression in the CeA. This aim will also investigate whether epigenetic mechanisms in the CeA underlie the effects of EE on chronic stress-induced visceral pain. ANTICIPATED OUTCOMES: In this application, we propose an approach that offers a novel way of thinking about chronic pain by using state of the art epigenetic techniques combined with classical behavioral outcome measures to identify mechanisms that will enhance our basic understanding of chronic pain. Under Specific Aim 1 we anticipate that there are unique central mechanisms driving female vulnerability for pain. We expect to show that heightened pain following chronic adult stress is modulated through epigenetically mediated mechanisms within the CeA, and that there will be significant differences between males and females. Under Specific Aim 2 we anticipate reversing the abnormal molecular events occurring within the CeA in response to chronic stress using environmental enrichment and investigate the importance of histone modifications to mediate the effects of environmental enrichment. RELEVANCE TO VETERANS HEALTH: Taken together the work proposed in this VA Merit grant will substantially advance our understanding of the neural and molecular level events responsible for chronic pain and taken together with our previous data provide a unifying central hypothesis for how stress leads to chronic pain. The VA provides specialized health care for veterans with chronic pain, however therapeutic options for pain relief are very limited and fraught with side effects. Scientifically, the results from this project will identify a novel stress-associated brain circuit, along with the specific neurotransmitters, that modulates chronic pain. Identification of the mechanisms and circuitry involved in chronic stress-induced pain could lead to new targets for therapies to treat veterans experiencing chronic pain, which is a significant unmet healthcare burden. Furthermore, since female veterans with anxiety-related disorders have higher rates of pain, our research will compare data from male and female rats in an attempt to identify novel mechanisms that may be unique to female veterans.